GnIH-induced mitochondrial dysfunction lead to oxidative stress and apoptosis in thyroid follicular cells, causing hypothyroidism.

Thyroid disorders profoundly disrupt metabolism, development, growth, pubertal timing, and fertility in domestic animals. Gonadotropin-inhibitory hormone (GnIH), a key inhibitory neuropeptide regulating reproductive function, has been implicated in metabolic dysfunction-associated infertility as well as thyroid dysfunction-related pubertal abnormalities. These observations suggest potential crosstalk between GnIH and thyroid hormones (THs), positioning GnIH as a possible integrative regulator linking the hypothalamic-pituitary-thyroid (HPT) and hypothalamic-pituitary-gonadal (HPG) axes. However, the role of GnIH in the modulation of thyroid function remains poorly defined. Using the pig as a translationally relevant model for neuroendocrine research, we investigated the peripheral effects of GnIH on TH synthesis and elucidated the underlying mechanisms in female piglets. Untargeted metabolomic analysis revealed a significant reduction in serum thyroxine levels following chronic intraperitoneal administration of GnIH compared with vehicle-treated controls. Furthermore, colocalization and pharmacological analyses demonstrated that peripheral GnIH directly suppresses TH synthesis in the thyroid gland, leading to decreased circulating TH levels and activation of the negative feedback regulation within the HPT axis. These results suggest that the thyroid gland is a primary peripheral target for GnIH-induced hypothyroidism. Subsequent in vivo and in vitro studies confirmed that peripheral GnIH disrupts mitochondrial function, inducing apoptosis and oxidative stress in thyroid follicular epithelial cells and ultimately causing hypothyroidism, while its effects on proliferation followed an opposite trend. These results establish that GnIH directly inhibits TH synthesis through mitochondrial dysfunction and follicular epithelial cell apoptosis, thereby contributing to hypothyroidism pathogenesis. Our study identifies GnIH as a novel neuroendocrine regulator of thyroid function and suggests that GnIH agonists or antagonists may offer therapeutic potential for thyroid disorders and related conditions.